Alice Pirola
AEROBIC TRAINING: EVIDENCE BASED OPTIONS FOR COGNITIVE PROTECTION AND ENHANCEMENT IN
PARKINSON’S DISEASE. A LITERATURE REVIEW.
Degree Programme in Physiotherapy 2015
AEROBIC TRAINING: EVIDENCE BASED OPTIONS FOR COGNITIVE PROTECTION AND ENHANCEMENT IN PARKINSON’S DISEASE
Pirola, Alice
Satakunnan ammattikorkeakoulu, Satakunta University of Applied Sciences Degree Programme in Physiotherapy
February 2015
Supervisor: Bärlund, Esa Number of pages: 49 Appendices: 10
Keywords: Parkinson’s disease, aerobic exercise, cognition
____________________________________________________________________
ABSTRACT
Context: the role of endurance physical activity of moderate and high intensity in Parkinson’s disease patients in their mild to moderate phase (Hoehn and Yahr scale:
I-III) regarding their cognitive functions.
Objective: determine the typologies of aerobic physical activity that scientific evi- dence has proved effective in enhancing and/or slowing down the decline of one or more of the cognitive domains as a consequence of the progression of Parkinson’s disease. Another objective is to assess whether a specific modality of aerobic exer- cise could be proved, more effective than the others in terms of cognitive preserva- tion, or even augmentation.
Data sources: this review has been carried out by searching the following databases:
PubMed, Cochrane Library and PEDro. Also, additional search has been carried out by screening the references of those articles already selected, in case other relevant articles would have been available from different sources. Search terms included:
“Parkinson’s disease”, “aerobic exercise”, “cognition”, “cognitive”, “endurance”,
“treadmill”, “BDNF” and “hippocampus”; these terms were inserted in the different databases search engines by connecting them with the Boolean term “AND”.
Study selection: the studies selected were all those examining any eventual relation- ship between aerobic physical activity, either alone or having a relevant major role in conjunction with other modalities of exercise, and the cognitive aspects of Parkin- son’s disease. The search was limited to years 2008 to 2014.
Data extraction: all the data were extracted from the selected material by the author of this thesis. The data that were taken into account were the method of research, the different types of implementations administered to the intervention group and the eventual sample group, the methods of assessment, the results and, when present the reasons of possible bias, including those expressed by the authors of the study them- selves.
Results: seven articles were included concerning moderate aerobic physical activity implementation in patients with Parkinson’s disease clinical diagnosis.
Limitations: the main limitation were the restricted amount of time, this necessary to present this thesis in the agreed amount of time. A further limitation was the possibil-
ity to access only to those articles which were free or requiring a minimum charge (<10 euros). Search strategy was also limited to only some databases instead of more comprehensive approach.
Conclusions: all the studies shared the conclusion that a regime of aerobic physical activity in a population of patients in their mild stages of Parkinson’s disease is sig- nificantly beneficial in enhancing and/or slowing down the decline of one or more of the cognitive domains. However, not all of the studies taken into consideration for this review reported the specific type of exercises included or the intensity range within which the activity had been proved to be effective. Future studies should re- port more accurately these details and include at least one assessment test for each of the subcategories of cognition in order to determine whether one aerobic activity can be objectively considered more efficacious than another in the ambit of cognitive preservation. A more detailed description of the activities implemented (including doses, intensity range and eventual modifications, where these had been applied) would also improve the accessibility of these results also to the public, patients and caregivers included. More thorough systematic review would be beneficial.
CONTENTS
1 INTRODUCTION ... 6
2 OBJECTIVES ... 8
3 PARKINSON’S DISEASE ... 8
3.1 Pathophysiology ... 10
3.2 Etiology ... 10
3.2.1 Environmental factors ... 11
3.2.2 Genetic factors ... 11
3.3 Epidemiology ... 12
3.4 Incidence ... 13
3.5 Diagnosis and classification ... 13
3.6 Motor symptoms. ... 15
3.7 Non motor symptoms ... 16
3.7.1 Cognitive impairments ... 17
3.7.2 Memory impairments ... 17
3.7.3 Attention impairments ... 18
3.7.4 Executive dysfunction ... 19
3.7.5 Visuospatial impairments ... 20
3.7.6 Behavioural deficits ... 21
3.7.7 Sleeping dysfunctions ... 21
3.7.8 Sensory dysfunctions... 22
3.8 Mild cognitive impairments anticipating dementia? ... 23
3.9 Dementia in Parkinson’s disease... 23
4 EXERCISE IN PARKINSON’S DISEASE ... 24
4.1 Aerobic exercise ... 24
4.2 Low, medium or high intensity, what is better?... 24
4.3 Effects of aerobic exercise on brain – how can aerobic exercise influence cognition? ... 26
4.3.1 Cardiovascular aspect ... 27
4.3.2 Immunological aspect ... 27
4.3.3 Trophic factors action ... 27
5 STUDIES SELECTED ... 28
5.1 Research history ... 28
5.2 Studies included ... 29
6 CONCLUSIONS FROM STUDIES REVIEWED ... 41
7 DISCUSSION ... 42
REFERENCES ... 44
APPENDICES
APPENDIX 1. Tests generally employed to assess dysexecutive syndrome APPENDIX 2. Articles grading according to PEDro scaling system
1 INTRODUCTION
Throughout the last decade, physical exercise has come into evidence as a way of treating and even preventing neurodegenerative conditions, Parkinson’s disease (PD) being one of those. Its benefits concerning this condition have been proven to span from the syndrome’s motor signs to, more recently, the non-motor ones. While it is now relatively easy to design a specific exercise plan addressed to the major motor symptoms a patient is exhibiting, the choice is not as clear cut when addressing the non-motor symptoms. Numerous studies on both animal models (Sung, 2012; Tuon, 2012) and human patients (from the initial to the mild phase of PD) are available nowadays supporting specifically the validity of aerobic exercise, usually in the form of treadmill brisk walking/jogging. What, according to the author of this thesis, still remains unclear, is whether a specific modality has been proved, so far, more effec- tive than another: in particular, when addressing the cognitive deficits of Parkinson’s disease, is a (relatively) high intensity aerobic training program more effective than a moderate one of the same type? Having some data concerning this difference may help on one side the patient and his/her caregivers to stay motivated in what should become a life style and not only a cure for a determinate about of time, and, where possible to upgrade it in intensity (provided that the benefits would largely outstand the risks). Similarly, further evidence of the neuroprotective role of aerobic activity would be an additional health promoting reminder of the importance of an active lifestyle at any age. Also, a clear display and perhaps a wider diffusion of the studies’
results, could positively influence the local competent committees to set funds to promote aerobic activity for this part of population. Finally, the author of this thesis finds of primary importance to make these results available for the population in- volved, which means the mere publication of results on specialized journals may not be enough: instead, translating them into a more accessible and understandable mean of information, such as a leaflet, for example, and giving more than one alternative for the activity to be taken up, may play a key role in involving more the patient him- self in his therapy: “why do I have to exercise?” or “it is too late/ I am too old” or “I do not like jogging” , “I cannot jogging for –put any reason here-“ and “it would not
make any difference now” would receive an answer in a layman language, leaving out technicisms.
2 OBJECTIVES
With this thesis, the author is aiming to present those exercises that clinical evidence has proved to promote an effective neuroprotective and/or neurotrophic action (ex- pressed as maintained or even improve cognitive functionality) in individuals affect- ed by Parkinson’s disease. The presence of this beneficial effect would have been assessed either by testing different domains of cognition or by laboratory tests meas- uring the BDNF serum levels. The following review has been organized according to the PICOS principles and the articles had been graded according to the PEDro scale for quality (although one of the articles included, being a single case report, was not particularly suitable for this type of rating).
The PICOS principles regard the population a particular treatment or therapy is di- rected to, the intervention(s) that have been applied, the control(s), whenever present, the outcome observed from the intervention and the study typology. Pertinently to this review, the PICOS principles have been established as follows.
Population: Idiopathic Parkinson’s disease patients; non-demented; in their mild to moderate stages of the disease (Hoehn & Yahr: from one to three).
Interventions: aerobic/endurance exercise or aerobic/endurance and other training modalities.
Controls: any other treatment or placebo.
Outcome: any cognitive outcome or any significant increase in BDNF serum levels.
Study design: RCTs, CCTs and single cases of study have been included.
Furthermore the author graded the articles included using the PEDro scaling system.
3 PARKINSON’S DISEASE
Parkinson’s disease was a condition already known for centuries as “Paralysis Agi- tans”, shaking palsy, when, in 19th century, it got its current name by the French neu-
rologist Jean-Martin Charcot, after Doctor James Parkinson, who first described it in a systematic way in the London of 1817 (Goetz, 2011).
Parkinson’s disease (PD) is a chronic neurodegenerative condition affecting, in prev- alence, but not exclusively, the dopaminergic neurons of the Substantia Nigra pars compacta (SNpc) (Jankovic, 2002) (see Picture 1).
Picture 1. Sagittal section of a brain, with indication of the Midbrain and the location of the Substantia Nigra. A sample of Substantia Nigra from both a healthy and Parkinsonian brain is shown (reference:
Dzamko, 2014).
This degeneration is often accompanied by intracytoplasmatic protein aggregates, the so called Lewy Bodies. Parkinson’s disease is considered to be an age-related dis- ease, although genetic autosomal, both dominant and recessive, forms of the syn- drome have been observed and studied throughout the years, these affecting a young- er minority of patients. Left out this minority, the majority of the patients is affected by the idiopathic form of Parkinson’s disease: for this, since no biomarker has yet been found, the diagnosis is based on hallmarks. (Jankovic, 2002)
3.1 Pathophysiology
Despite the progresses in brain imaging and neurology in general, most cases of PD, have no specific causes, therefore the denomination of “Idiopathic PD”; what it is known, however, is the pathophysiology of this condition. Idiopathic Parkinson’s disease is characterized first of all by the depletion of dopaminergic neurons, mainly in the substantia nigra pars compacta (Zigmond, 2002). It has been proven, though, that the very first areas where the condition develops are others, precisely the vagus nerve (dorsal motor nucleus), the olfactory bulbs and nucleus, the locus coeruleus and only then the substantia nigra (Kwan, 2011).
In order the PD hallmark symptoms and signs to develop, a major depletion of do- paminergic neurons has to occur: this because, in the first phases, some compensato- ry mechanisms (e.g. increase in the amount of dopamine synthesis and release in the remnants neurons) may still permit a normal functioning. With time, catechola- minergic systems other than the dopaminergic can be involved, causing the devel- opment of additional symptoms, including cognitive decline and dementia. (Zig- mond, 2002)
A second characteristic, pathological sign of this condition is the presence of intra- cellular aggregates, denominated Lewy Bodies: these are of proteic and lipidic nature and can be observed, particularly, in those areas showing neural loss, although the relationship between these two phenomena is not fully understood (Cookson, 2009).
Furthermore, it must be evidenced the presence of α-synuclein as component of the Lewy bodies in those individuals who suffered from idiopathic PD: this protein, which retains the propriety to self-aggregate in a not dissolvable fashion, is involved in the development of the Parkinson’s disease, although to which exact extent is still not known (Zigmond, 2002).
It must be kept in mind, however, the fact that neither the neural loss nor the pres- ence of these aggregates are sufficient determinants of the disease (Cookson, 2009).
3.2 Etiology
Despite the fact PD is diagnosed in the later decades of life, aging has not proved to be an etiologic factor for this condition. This is supported by the fact that striatal and
nigral dopaminergic neurons depletion occurs with different times and modalities in PD patients and healthy subjects. (Zigmond, 2002)
In the etiology of idiopathic Parkinson’s disease both environmental and genetic fac- tors have been hypothesized (Keus, 2014).
3.2.1 Environmental factors
Some environmental factors have been related to an increased risk to develop PD, there are most importantly, the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) being the most important. It causes symptoms so similar to those of PD and it has been used to create laboratory models of PD up to now. Also, other environmental factors recognized are exposure to well waters, pesticides (Rotenone), herbicides, industrial chemicals and metals, particularly long term exposure to man- ganese, copper, alone or in combination with lead and/or iron. (Gorell, 1999)
Viral etiology has been proposed for years, without ever coming to a satisfactory conclusion, not even with the encephalitis lethargica pandemic of the years 1916- 1926 which caused in many of the (few) survivors what it is agreed now to be a well distinct condition, currently named “Postencephalic Parkinsonism” (Jankovic, 2002).
On the other hand, smoking and any form of caffeine seems to have inverse correla- tion with the risk of developing PD (Jankovic, 2002), while the results concerning the integration of antioxidants in the diet has given mixed results: for instance, to- copherol (vitamin E) assumption has proven not to be determinant in the prevention of the disorder (Molina, 1997).
3.2.2 Genetic factors
At first, different genetic mutations have been found to cause parkinsonism; howev- er, the same studies helped to better understand the mechanisms behind idiopathic Parkinson’s disease as well (Huang, 2003). As the website of Parkinson’s disease Foundation (2015) reports, two categories of genes can be individuated concerning idiopathic PD etiology: “causal genes” which are proven to be enough to cause the disease, even without co-factors and “associated genes” which, although not directly causing the condition, predispose an individual to develop it.
Causal gene for PD is the one called SNCA, abbreviation for “synuclein, alpha (non A4 component of amyloid precursor)”, belonging to the PARK family of genes: it carries the instructions for the synthesis of α-synuclein. When SNCA shows some mutations (at least 18 mutations have been reported), this causes the production of misfolded or excessive α-synuclein, which in turn has been shown to be connected to the pathophysiology of PD. (Website of the Genetic Home Reference, 2012) This form of PD, however, remains very rare, involving about one or two percent of the clinical population (Website of Parkinson’s disease Foundation, 2015).
Associated gene for PD is that named LRRK2 (“Leucine-rich repeat kinase 2”) re- sponsible for the synthesis of the protein dardarin; the modifications this gene may exhibit are manifold, as well as the consequences in case of developing PD: age of onset spreading from the 30s to the 80s, disease-specific dementia development, etc (Website of Parkinson’s disease Foundation, 2015)
However, it must also be taken into consideration that individuals belonging to the same familial nucleus and who developed the condition shared not only the genetic pool, but also similar behaviors and environment: therefore familial occurrence of any form of Parkinsonism may be due not only to genetic factors (Jankovic, 2002).
3.3 Epidemiology
According to the European Parkinson’s Disease Association (EPDA), about 6.3 mil- lion people are currently diagnosed with Parkinson’s disease worldwide.
In particular, Keus reports in 2014 that 1.2 million people are estimated to be affect- ed with this condition throughout whole Europe. The same guideline predicts that, given the ageing rate of the population, this current number is destined to be doubled by 2030, while, for the incidence, the disease ratio is 1.5 times higher in men than in women. With the exclusion of some genetic forms of this condition, which have been observed to affect individuals even younger than 40 years old, the majority of diag- nosis Parkinson’s disease is made in persons over the age of 60 years: this may be due, at least in part, to repetitive, prolonged exposure to predisposing factors (some of them have been listed before in this thesis), together with a decline, partly physio- logically age-related, of the neurological repair and of those mechanisms responsible for toxins and oxidation byproducts disposal (Jankovic, 2002).
3.4 Incidence
Only few surveys (Dorsey, 2007) have been carried out about Parkinson’s Disease prevalence at worldwide level: the results indicate the prevalence of this condition varies widely from one area of the globe to the other, although this is due to a com- plex combination of factors, such as age distribution and life expectancy in that spe- cific population, methods of diagnosis, possibility of access to health care facilities and to exposure to either predisposing or protective environmental factors (Muangpaisan, 2011). It has been estimated that PD is 1.5 – 2 times as common in men than women of similar age, independently from geographical location and/or race: this may be caused by multiple factors, such as greater exposure to environ- mental risk factors, for instance those activity-related, different hormonal influence and ultimately, genetic mutations predisposing to the condition, which mostly occur on the X chromosome (Wooten, 2004). As for age distribution, PD is more common after the fifth decade of age, up to the age of 90, when it is seen to decline again, probably due to the small of this part of the population (de Lau, 2006).
3.5 Diagnosis and classification
Parkinson’s disease often presents with one or more typical hallmarks: bradykinesia, tremor at rest, often asymmetrical and starting from a very specific area (a finger, for example, where it can present also in a “pill-rolling”-fashion), muscle stiffness, with consequential difficulties when walking and, more in general, moving; also, impaired posture, mask-like face and micrographia are often present (Sharma, 2013). Diagnos- ing Parkinson’s disease at an early stage is very difficult; on the other hand, with time and the development of the condition, the signs and symptoms become more evident and numerous (Calne, 1992). According to Hughes (1992), the diagnosis of Idiopathic Parkinson’s disease is carried out throughout three phases: in the first phase, the patient is referred to a specialist (usually a neurologist), in order to deter- mine whether his/her symptoms and signs do actually fall into the wider group of parkinsonisms (which includes the ones listed just above); secondly, other possible causes for the patient’s condition will be ruled out, including head traumas, history of stroke, cerebral tumor, exposure to neurotoxins, the assumption of antipsychotics
and/or drugs affecting the uptake of dopamine, history of encephalitis, or other neu- rological conditions.
Further evidence for Idiopathic Parkinson’s Disease will be sought, instead, in the third phase of the diagnostic process; in particular, three or more of the following signs should be observed:
unilateral onset, together with perseverant asymmetry of the motor symp- toms (or with the side where the onset took place being most affected);
resting tremor;
the disorder being degenerating progressively;
significant excellent response to levodopa, which, on the other hand, can be responsible of peak dose dyskinesia and/or chorea;
significant responsivity to levodopa for ≥5 years.
According to the degree of disability shown by the patient at the moment of the neu- rological examination, a classification of the stage of the condition can be made; the Hoehn and Yahr classification scale is the most used in clinical settings, mainly be- cause of its easy and almost immediate applicability (see Table 1).
Table 1: Hoehn and Yahr scale, detail. (Bhidayasiri, 2012)
However, right because of this simplicity and the exclusive focus on motor symp- toms and their consequences on the daily life, it must be always kept in mind that this scale is not comprehensive and bears no indication of non-motor symptoms. A modi- fied version of this scale had been designed, including two further stages between grades one-two and two-three. However, despite the availability of this modified ver-
sion, it is recommended to evaluate the context and the purpose of a given research to be carried out before opting for one or the other version. (Goetz, 2004)
3.6 Motor symptoms.
The most recurrent clinical signs of PD are bradykinesia (present in 77-98% of cas- es), resting tremor (evident already in the beginning phase of the disease about in 70% of cases, increasing then up to 100% of cases in the later stages); rigidity through the whole passive ROM, often accompanied by pain, is also common, recur- ring in 89-99% of cases: this, in turn, may cause antalgic postural misalignment.
(Keus, 2014). Furthermore, other hallmarks of the condition, although occurring usu- ally in the later stages, are the loss of postural reflexes, these causing balance im- pairments. One exemption, which can be evident even three years after the diagnosis, is the deterioration of the dynamic postural control, evidenced, in clinical assess- ment, by asking the patient to turning of a 180 degrees angle (Keus, 2014).
In addition, patients suffering either from idiopathic Parkinson’s disease or a form of Parkinsonism can exhibit also an irregular posture, in particular in the areas of neck, limbs or trunk; this is true for about a third of the patients, who most often present with a pathological flexion at hip and knee level, accompanied by shoulder protrac- tion; other, postural anomalies can be encountered in this population of patients:
camptocormic posture (see Picture 2), pleurothotonus/Pisa’s syndrome, antecollis and scoliosis are more serious and more disabling, whose cause, in relation to the Parkinson’s pathology, remains unsure, thus making its management challenging.
(Doherty, 2011)
Picture2: Camptocormic posture (reference: http://en.wikipedia.org)
Nevertheless, the ultimate confirm of the diagnosis will be possible only postmortem, by observation of the pathological signs such as the presence of alpha-synuclein positive Lewy bodies and the loss of pigmented neurons, particularly in the substan- tia nigra pars compacta (SNpc). These motor hallmarks however, which, on average, will start to be evident only after about 50% of the dopaminergic neurons in the SNpc have been lost, are often the main target in PD treatment. The therapy for PD, in fact, mostly consists in replacing the lack of dopamine, due to the degeneration of those neurons responsible for its production, at first throughout dopamine agonist drugs and, later on, by adding Levodopa (L-dopa), a precursor of dopamine. Levo- dopa will act on those motor hallmarks, but it will not affect other important common features often present in PD, such as freezing of gait, autonomic, cognitive, behav- ioral and affective dysfunctions: on the opposite, besides other side effects, Levodo- pa, more likely, will trigger or exacerbate some of them. (Sethi, 2008)
3.7 Non motor symptoms
Despite PD is diagnosed by the presence of clinical motor signs listed above, the
“non-motor” deficits are just as important as the first ones, and just as well they can influence the quality of life of the patient and his/her family or caregivers, besides being one of the main reasons for a PD patient institutionalization. Under the term
non-motor symptoms is collected a heterogeneous group of dysfunctions, in particu- lar related to cognitive, memory, attention, executive, visuospatial, autonomic and behavioral areas. It has been observed that patients exhibiting non-motor symptoms of Parkinson’s disease tend to be particularly more affected in one of these domains.
(Litvan, 2011)
3.7.1 Cognitive impairments
Throughout the years, studies on both animal and human subjects have brought the scientific community to the observation that basal ganglia dysfunctions are one of the causes of cognitive and behavioral dysregulations.
Concerning the cognitive domain, the main consequences from basal ganglia dys- functions include a general slowing down in the processing of all the information re- trieved from the environment, an inefficient retrieval of memories (sometimes more than actual memory loss), an impaired executive capacity and behavioral symptoms such as inertia, apathy and depressed mood (Jankovic, 2002).
Put together, these signs make up what are the most recurrent observation and com- plaints made by the family or the caregiver of the patient: forgetfulness, difficulty to concentrate (or “set maintenance”) and the difficulty in following conversations with more than one interlocutor (Jankovic, 2002).
In the following paragraphs, the main cognitive areas, found to be most commonly impaired at some level in individuals suffering from PD, have been illustrated; as it shows, cognitive impairment in PD, although very common (up to 93% of the clini- cal PD population, according to Pillon, 2001) and present from the very early stages of the disease, is more likely to interests very specific domains of cognition, these being memory, executive and visuospatial capacities.
3.7.2 Memory impairments
Memory is not a uniform one-way process. Research in the years has only been able to partially clarify the mechanisms behind it. In PD patients, both the “working memory” and the “long term memory” can result impaired. Working memory, that part of memory with the function of retaining newly acquired piece of information
waiting to be “filtered” and manipulated before being stored by the long term one, can result impaired by PD, also due to the incapacity or inefficiency of repressing secondary, interfering stimuli. This can be proved, for example, by poor results in short term recall tasks (eg. remembering as many items from a list) (Jankovic, 2002).
Long term memory, on the other hand, can result impaired as well; the temporal-lobe controlled “strategies” aimed at storing the information, do not result particularly af- fected in this category of patients, while, on the other hand, the organization, either temporal or according to other different associative conditions, can result impaired.
Further inefficiencies can be recognized in the procedural learning, at variable ex- tents, and in the internal control of attention, which also contributes to the inefficien- cy at maintaining the attention to given stimuli. (Jankovic, 2002)
3.7.3 Attention impairments
Attention can be defined as the voluntary decision to select one particular infor- mation, whether of the visual, auditory or any other sensory type, while ignoring as not important other stimuli occurring at the same time, in the same circumstance. At- tention should not be confused with the concept of “arousal”, which, however, can be affected in Parkinson’s disease patients: while arousal describes a global attentive- ness and readiness, which can be opposed to apathy, with “attention” clinicians refer usually to the conscious and voluntary choice to focus on a particular subject. (Selzer
& Clarke, 2006). The psychologist William James wrote, back in 1890, that attention requires “withdrawal from some things in order to deal effectively with others…”.
Similarly, attention may play a relevant role in the learning process by helping ad- dressing the subject’s mind on the task or notion that needs to be acquired (Selzer &
Clarke, 2006). Cognitive impairment, including the attention functions, is not influ- enced by dopamine levels alone, but more likely, by a precise equilibrium between dopamine, noradrenaline, serotonin and acetylcholine: this translates into the fact that the dopaminergic treatment addressed at the motor symptoms will be of no effect in addressing the non-motor ones (Solari, 2013).
3.7.4 Executive dysfunction
Executive function can be regarded as an “umbrella” term, comprehensive of differ- ent cognitive processes, such as setting the attention on a specific thing, maintaining this attention as long as it is necessary, flexible thinking, necessary to adapt ourselves efficiently to the ever-changing situations and also, once sat a goal, the capacity of the individual to act and behave according to that outcome requirements. This being said, it is clear how many different cognitive functions are necessary to maintain an efficient executive capacity. As a consequence of this quantity of different facets of cognition, many different specific tests will be needed (some of which will be further illustrated in appendix one), in order to conduct a satisfactory assessment of this sphere of cognition. The evidence we obtain from clinical settings (tests, scans, fmri,…) has stressed the importance of the frontal lobes in the ambit of disturbances and impairments of the executive area of cognition: this mainly because of the vast network of reciprocal links between cortical and subcortical strata in this specific ar- ea of the brain, which would act as “supervisor” and “modulator” of the myriads of connections existing. Eventual frontal lobe damages are seen more in the everyday life than in the results coming from the most commonly used intelligence tests; in particular, some difficulties and impairments are observed more often in these indi- viduals’ daily lives. Firstly, the patient is not able or has anyway difficulties in modi- fying his behavior accordingly to changing situations/stimuli, as it can be evidenced by the “Wisconsin Cards Sorting out Test”. Secondly, in his daily life, the patient encounters difficulties in carrying out tasks composed by more than one finite action:
the problem in these circumstances is not represented by the single “steps” making up the task as a whole, the difficulty resides instead in the capacity from him of plan- ning and handling the “steps” as a sequence. Thirdly, the patient may result unable to sort out from a group of concomitant stimuli the single, most important one, and fo- cus on that the response; this incapacity of telling the important stimulus from the secondary distractors can be assessed by the “Stroop Test”; it is also a primary cause of what is defined “Environmental Dependency Syndrome”, a condition in which the subject feels composedly forced to take and use any object he may see in a given set- ting, although not asked to do so. Fourthly, the perseveration of a behavior, whether vocal or motor and even if as response of a previous stimulus is an indicator of pos- sible dysexecutive syndrome, causing the patient to be unable to voluntarily suppress
that behavior. Lastly, an impairment that can be added as part of the dysexecutive
“spectrum” is memory dysfunction: in PD patients this impairment does not affect directly the working memory itself, rather the problem resides more in attention defi- cits and/or inefficient retrieval strategies of these memories. Retrieval, in particular, requires a conscious effort, a strategy, and it is this organizational aspect that the PD patient is inefficient at, with the result of appearing forgetful to family and caregiv- ers. (Jankovic, 2002)
The tests (see “Appendix 1” for some of current use), generally adopted for these reasons in clinical settings, are all evaluating the frontal lobe functions, in particular the formation of concepts, the individuation of implicit rules (“Wisconsin card sort- ing” test and “Spatial delayed response” task), problem solving skills (“Tower Task”-like tests), the capacity of set shifting (“Trail making” and “Odd man out”
tests) and, on the opposite, the ability to maintain a given mind set and therefore in- hibiting interferences (“Verbal fluency” and “Stroop” tests). However, dysexecutive syndrome, as it is observed in PD, is a condition which can have different presenta- tions, accordingly to the area of prefrontal cortex of major (or exclusive) affection. In particular, a major dorsolateral prefrontal cortex damage will cause the most severe cognitive deficits, while a major or exclusive disruption in the orbitofrontal cortex, having connections to the limbic region, will be reflected more as an impairment in the affective and social capacities. (Jankovic, 2002)
3.7.5 Visuospatial impairments
Despite clinical evidence (Tachibana, 2013; Aarsland, 2011) stated some connection between PD and visuospatial dysfunction, the main belief is that this impairment may be due primarily to the high cognitive demand that the tests used to ascertain it re- quires the patient: in these occasions, in fact, the patient is asked to perform tasks that also require a cognitive level that the syndrome may already make difficult to reach (for example, the capacity of centrally processing the various stimuli presented at the same time, or set shifting). Always in the field of visuospatial impairments, further impairments have been detected in the preattentive visual processing system, the unconscious collection of all the concomitant environmental stimuli destined to be filtered by importance by the brain. (Jankovic, 2002)
3.7.6 Behavioural deficits
Mood and behavioral changes are often reported as features of PD: introversion, ob- session with control of any life aspects, hypervigilance and caution, especially when finding himself in unusual situations, repression of strong emotions leading to apathy are the most commonly reported ones. Depression may also develop, together with and not as a consequence of the disease, since it is not strictly related to the stages of PD. However, the development of depression should require further attention, since evidence suggest this state may trigger, at first, attention and memory impairments, and then depressive mood can contribute to the development of dysexecutive syn- drome. (Jankovic, 2002)
3.7.7 Sleeping dysfunctions
The disturbances in the sleeping REM phase, defined as “REM sleep behavior disor- der” (RBD) have been already identified as one of the anticipating signs of a diagno- sis of Parkinson’s disease, as well as other synucleinopathies. Other sleeping dys- function, including insomnia and excessive drowsiness during the daytime are being investigated as other possible warning signs of a future diagnosis of Parkinson’s dis- ease. (Manni, 2007)
The REM sleep behavior disorder has also been observed to accompany PD through- out its course, particularly those forms characterized by a quicker progression of the cognitive aspects, often into PD-specific dementia. In addition, RBD is associated with a significant likelihood of the patient presenting with concurrent visual halluci- nations. Furthermore, the breathing pattern throughout the whole sleeping cycle, both REM and non REM phases, could result dysfunctional, with temporary, often period- ical events such as sleeping apneas and/or hypopneas (this latter one indicating sig- nificant reduction in the amplitude of the breathing pattern): this phenomena, defined as “Sleep Disordered Breathing” (SDB), have been shown to further make the patient prone to neuropsychological and cognitive impairments, including memory (both short and long term), logical functions and frontal activities. (Manni, 2007)
3.7.8 Sensory dysfunctions
Parkinson’s disease patients may present either with hyposomia or anosomia. Olfac- tory functions (smell detection, its source identification and the ability to discrimi- nate one smell from the other) result impaired very early in the course of the disease, preceding by years the degeneration of the Substantia Nigra and the consequential motor signs and symptoms. (Antonini, 2012)
Furthermore, the high recurrence at which this category of impairments occurs (at least 90%) makes it a significant contributor in differentiating idiopathic Parkinson’s disease patients from those suffering from other forms of parkinsonisms (Doty, 2012).
In the recent years, dysfunction of other sensory systems have been taken into con- sideration in the ambit of Parkinson’s disease. Visual functions can result impaired in PD at different levels, either due to the increased risk of developing glaucomas, or as a consequence of the depletion of dopamine, which has been found to play a role in the organization of receptive fields and of the photoreceptors. These impairments can result in reduced visual acuity, in particular in contrast discrimination, colors recog- nition, as well as abnormalities in the eye movement, as in smooth pursuit move- ments, particularly along the vertical direction, together with a general reduction and jerkiness of eye movements; it has also been noted PD patients tend to exhibit a re- duced blinking rate, this in turn contributing to the “expressionless” mask-face, to- gether with dry eyes and generally a reduced vision; however, given the overlapping results between PD patients and healthy controls of the same age, further research is auspicable before considering them as possible biomarkers. (Armstrong, 2008) Hearing could be also involved in the evolution of this condition, as suggested by a study reporting a major frequency of hearing impairment in this category of patients when compared with healthy controls of the same age (Vitale, 2012). Studies con- cerning this subject, though, are still limited in number, thus not providing yet a clear evidence on the possible link between Parkinson’s disease and hearing impairments.
3.8 Mild cognitive impairments anticipating dementia?
These deficits will ultimately develop in dementia, though only a small percentage of the cases (about 25%) will be clinically recognized as such (Svenningsson, 2012).
Despite the onset time of dementia can be extremely variable from one patient to the other (it can either be few years after Parkinson’s disease has been clinically diag- nosed, to decades after), it has been observed that after dementia has sat in, the Par- kinson’s syndrome will progress to its terminal stage in a typical average timing of three years. This being said, since early cognitive impairments can be the prodromes of dementia in Parkinson’s patients, it is important not only to establish better criteria to define mild cognitive impairments, but also to draw an optimal therapy that can enable the patient to at least slow down this decline. Exercise has drawn attention as a possible side effects-free way. (Svenningsson, 2012)
3.9 Dementia in Parkinson’s disease
As already stated, cognitive decline in Parkinson’s disease follows the motor symp- toms (on the opposite, in Dementia with Lewy Bodies, the cognitive deficits pre- cedes the motor ones) and with a rate which is slower in the earlier stages of the dis- ease; nevertheless, once dementia sets in, the progression will follow a rather regular course: both physical and cognitive decline will progress into the terminal stage for about three years, with patient’s death.
The time of onset of dementia can vary a lot: some patients will develop dementia few years after PD has been diagnosed, while for others it may take decades.
It has been observed that a faster cognitive impairment (meaning a quicker develop- ment into dementia) occurs:
in patients whose PD has been diagnosed in later age;
in patients whose motor symptoms are mostly of the non-tremor type (in par- ticular relevant postural instability and disturbed gait);
in patients whose non-motor symptoms include hallucinations, behavioral and REM sleep phase disturbances and pronounced olfactory dysfunction.
One of the challenges relies right in the difficulty of adopting clear and unified standards to define and diagnose mild cognitive impairment in PD: for this reason,
the Movement Disorder Society has been the first to propose the criteria that have received clinical consensus. (Litvan, 2011)
4 EXERCISE IN PARKINSON’S DISEASE
4.1 Aerobic exercise
The definition of “Aerobic Exercise” applies to any intentional physical activity “us- ing large muscle groups and maintained continuously with rhythmic pattern”
(Hanson, 1988).
Also, aerobic physical exercise can be differentiated in three main typologies;
“Group 1” includes those physical activities which provide a constant bout of intensi- ty - and the consequential energy consumption – independently from the individual’s skills in that very activity: examples of “Group 1” activities would be brisk walking, cycling and even jogging. “Group 2” activities would be those which energy costs can register significant variations depending on the skills of the performer, as, for example, swimming or dancing. Wide variations in energy consumption from one performance to the other, instead, will be observed in those activities and sports such as football or tennis. (Kravitz & Vella, 2002)
4.2 Low, medium or high intensity, what is better?
Despite the studies carried out on this subject, the terminology concerning the physi- cal exercise intensity level is still cause of imprecisions and misunderstandings; in order to provide the patients, especially those with limited experience in the sport field, a clear indication of the intensity of physical activity that would best suit their specific status, thus avoiding both under and over training, some standardization of the basic terminology for physical activity should be achieved.
The basal metabolism, the minimum amount of energy an individual’s body requires in order to carry out its life functions in a physiological fashion is increased, at dif- ferent levels, by any activity taken up by the subject; this increment occurs with any
activity of the living, from the very basic sleeping, up to the highest level of physical activity, that of the elite athletes. This increment in energy needs has been divided by Norton (2010) into five major ranges: sedentary, light, moderate, vigorous and high intensity. Activities can be classified into one of those categories according to either objective, subjective and descriptive measures. Objective measures are those ex- pressed through METS (metabolic equivalents, 1 MET = 3,5ml O2/kg/min), HRmax
(which can be either measured or more, quickly, though less precisely calculated with the formula: 220 – age), HRRmax (where HRR, heart rate reserve, is calculated:
HRmax – HRrest), a safer threshold for calculating exercise intensity with less fit pa- tients, or, finally, VO2max (which is the maximum quantity, volume, of oxygen con- sumption, a very specific amount for each individual, not likely to change even with physical conditioning). Subjective measures, though less precise, are often used be- cause considered more accessible to the patient, in particular when this is not so ac- quainted with physical exercise. One form of subjective measurement is that provid- ed by the use of the Borg RPE (Rated Perceived Exertion) scale: throughout it, the patient can indicate his level of fatigue, with 6 (zero) being the lowest level (corre- sponding to the same fatigue that lying in bed would cause) and 20 being the highest (the same fatigue of a maximal, “all out” exercise) anytime during the activi- ty/exercise session. Finally, the same “Position Statement” indicated a third category of measuring the level of exercise intensity, that of descriptive measures: these take into account some common reactions that can be observed at a given exercise intensi- ty, like changes in breathing path, the capacity of maintaining the same intensity for 1’ or less, the capacity to hold a conversation at the same time without running out of breath, etc). (Norton, 2010)
Despite the arguable choice of selecting overlapping limits for all the objective measures, the following table summarizes in an efficient visual way the results of the review conducted by Norton and colleagues on the terminology and categorization of aerobic exercise adopted in the scientific literature.
Table 1. Categories of exercise intensity and the objective, subjective and descriptive measures ac- companying each category. (Adapted from Norton, 2010)
4.3 Effects of aerobic exercise on brain – how can aerobic exercise influence cogni- tion?
In these last decades many studies (Erickson, 2009; Bass, 2013) have been undertak- en in order to assess the correlation between physical activity and cognitive func- tions: across all the ages, from children to the elderly, healthy or already affected by cognitive dysfunctions (often age related), the results have proved this correlation to exist and to be particularly strong.
What still have not been fully understood and documented is the causal relationship:
how this beneficial documented effect of increased physical activity on specific areas of cognition is reached? Four main hypotheses have been individuated, these being:
cardiovascular, immunological, trophic factors (and their modulators) and fourthly, the neuroendocrine effect. (Phillips, 2014)
4.3.1 Cardiovascular aspect
Concerning the relationship between cardiovascular effects of increased physical ac- tivity and cognitive functions, the improved hemodynamics, particularly that of those vessel supplying the brain area with oxygen and nutrients (and taking the “wastes”
such as reactive oxygen species, or ROS, for example), consequential to higher levels of physical activity was associated with an inferior rate of gray and white matter loss.
(Colcombe, 2003)
All this evidence appears to be of particular strong relevance in the elderly popula- tion (while the connection cardiovascular fitness improvement and cognition is not as clear cut in average, in the younger populations). (Lautenschlager, 2008)
4.3.2 Immunological aspect
The extent of the immunological effect will depend on the duration as well as the in- tensity of the physical activity carried out by the individual; these beneficial effects will often include a general boost of immune function and increase in anti- inflammatory factors. This immunological enhancement is fundamental, as evidence proved that inflammation, when reaches chronic levels can be a cofactor to neuro- degenerative conditions (Parkinson’s disease included) as well as to cognitive im- pairments. (Gleeson, 2011)
4.3.3 Trophic factors action
Neurotrophins are among the possible reasons explaining the beneficial effect physi- cal activity can promote in terms of cognitive functions. Different polypeptides be- long to the category of neurotrophins, and among these, the brain-derived neu- rotrophic factor, or BDNF, is the most spread within the brain, particularly in the hippocampal region, which role is fundamental in learning and memory functions
(Phillips, 2014). Furthermore, BDNF retains a fundamental role in the survival of neurons, by influencing growth, differentiation and maintenance in general (Reich- ardt, 2006). It has also been observed that BDNF is fundamental in preventing hip- pocampal neuronal cells death and its plasma levels have proved to be a valid bi- omarker when assessing memory impairments (Pringle, 1996; Komulainen, 2008).
Evidence shows that physical activity, when in moderate intensity, is positively and significantly linked to raised BDNF serum levels, and this increase has been ob- served to persist for up to seven days after the physical activity session. (Coelho, 2014; Berchtold, 2005). However, the specific causes of this increment have not, so far, been clearly recognized. On the other hand, as scientific studies (Taverniers, 2010) have shown, high intensity levels of physical exercise lead more to damages than benefits; this can occur in two ways: either by lowering the anti-oxidant factors count or by increasing the levels of the hormone cortisol. The brain, in fact, is re- sponsible for at least the 20% of the whole oxygen consumption and this, together with brain low anti-oxidants levels already under physiological conditions, makes the central nervous system particularly vulnerable to the consequences of oxidative stress and their byproducts, as the so called “Reactive Oxygen Species” or ROS (Ut- tara, 2009).
5 STUDIES SELECTED
5.1 Research history
In June 2014 the search of studies for this thesis was carried out accessing PubMed database. An “advanced search” was chosen by inserting the terms "Parkinson’s”
[Title/Abstract] AND "exercise" [Title/Abstract] AND "cognition” [Title/Abstract].
Search resulted in 17 articles. The following restrictions were applied at first: studies dating back to the last ten years, their subjects being “humans” and the studies being available in English and in free full text. Out of the initial 17 articles, 11 passed this first selection; then, the author reviewed all the abstracts of these 11 results in order to assess the ones that complied with the PICOS principles established beforehand and listed above: it resulted that four studies could be included in this thesis. In this
second phase of the search, reviews concerning the topic were excluded from the thesis material: however, these were kept into consideration as an eventual source of other articles that for any reason had been not included in PubMed. In an analogue fashion, Cochrane Library and PeDro databases were searched, leaving out of the results eventual duplicates, already included from the PubMed search. This being said, a total of seven studies had been selected for this thesis; these will be summa- rized in the following paragraph.
5.2 Studies included
The seven studies selected have been collected in the following two tables. In the first table (Table 2), the type of study, PEDro rating, intervention and the different treatment plans administered in the sample and control group had been summed up.
In the second one (Table 3), the modalities of assessment, the final results and the eventual causes of bias have been described.
Table 2. Intervention plan, PEDro grading, sample group and control group implementations.
Title, Authors and Type of Study
PEDro Grade
Intervention Sample Group Control Group
1) ”Benefits of physical exercise on executive functions in older people with Parkinson’s Dis- ease”
(Tanaka, 2009)
Study
7 Multimodal exercise program VS same daily routine.
Participants qualified for the study when:
•Clinical PD from 1 to 3 in Hoehn
& Yahr scale.
•No signs of dementia.
•Haven’t taken part to any exercise program.
•Attending min. 70% of the pro- gram they are assigned to.
5 women, 5 men.
Multimodal exercise program for elder- ly with PD: basic aerobics.
60’ sessions, 3/week.
The program consisted of six parts of increasing load, each made of 12 ses- sions, lasting one month/each.
Each session was divided in 5 parts (warm-up; pre-exercise stretching; ex- ercise session; cool down; post exercise stretching).
HR: 60-80% HRmax (only one partici- pant/session had a HR monitor)
6 women, 4 men;
CG participated already as control group in another study in the same structure.
This control group (CG) was asked to maintain the same daily routines, without joining any exercise program
2) “Phase I/II random- ized trial of aerobic ex- ercise in Parkinson’s disease in a community setting”
(Uc, 2014)
6 Four different training methods:
1_individual and continuous train- ing;
2_group continuous training;
3_individual interval training;
4_group interval training;
The study was conducted throughout three years.
Initially, during the first two years, participants were randomized into 4 different training methods:
1_individual and continuous training;
2_group continuous training (only in
No control group.
Randomized trial the first year);
3_individual interval training;
4_group interval training (only in the first year).
Then, on the third year, the study fo- cused only on continuous, individual training.
3) “The effects of adapted tango on spatial cognition and disease severity in Parkinson’s disease”
(McKee, 2013)
Study
7 • Adapted Argentinian Tango.
• Patient education in the form of seminar.
n pts = 24 H&Y: I-III
2x90 min./wk for a total of 20 sessions of adapted tango.
Each class: 20’ standing warm up and practice of the steps already learnt;
then new steps were added, strictly according to the manual, and after that those were integrated with the older ones.
During the partnering phase, each pt both conducted and followed, though always paired with non PD partner.
n pts = 9 H&Y: I-III
2x90 min./wk educational sessions for a total of 20 sessions.
Health-related topics with medical students and professors. 1hr+30’ discussion.
4) “Exercise and Parkin- son’s: benefits for cogni- tion and quality of life”
(Cruise, 2011)
Study
4 • Exercise Intervention Program (EIP, n=15)
• Control group (n=13)
n pts =15, 2/wk for 12 wks.
Each session (60’) always included both aerobic and strength training.
Each session included:
• 5’ warm up (low intensity aerobic activity such as walking, stationary cycling and stretching).
• Resistance training: 6 exercises for
n pts =13,
maintained its usual lifestyle for 2/wk for 12 wks.
Baseline and follow-ups carried out always during the “on” phase.
both upper and lower body major groups.
• 25-30’ aerobic training: stationary cycling, rowing, treadmill at 60-85%
HRmax.
The intensity of the exercises was in- creased gradually throughout the ses- sions.
5) “Can exercise im- prove language and cog- nition in Parkinson’s disease? A case report”
(Nocera, 2010)
Single Case Report
(4)* 8 weeks of aerobic exercise as sin- gle and dual task.
Intensity: starting from 50%
HRRmax, increased by 5% every week up to 75% HRRmax.
Subject of the study: woman idiopathic PD for 11yrs 66 y.o.
H&Y: 2 UPDRS: 31/106 dx-handed
Aerobic Exercise in the form of sta- tionary ergometer in single and cogni- tive dual task.
Therapy delivered for 8 wks,
3times/wk, for a duration of 20’ each.
No control group
6) “Efficacy of a multi- modal cognitive reha- bilitation including psy- chomotor and endurance training in Parkinson’s disease”
(Reuter, 2012)
Clinical Study
8 Random allocation to group A, B or C, (C being the “sample group”) with different combination of cog- nitive, transfer, psychomotor train- ing, plus occupational therapy and relaxation sessions to reach the same amount of therapeutic inter- ventions in each group.
The study was structured in 2 phases:
Period 1: 4wks, at the rehabilitation unit. Physiotherapists, occupational
240 pts
male and female
Age: 50-80 y.o. (average 64±4 yrs)
Diagnosed w/ PD
(average diagnosed 8 before)
Mild Cognitive Impairment (MCI) in- clusion criteria
Patients did not differ demographically
Two control groups, group A and group B.
Group A:
exclusive cognitive training
(plus to reach same amount of training time of group C, relaxation and occupational training)
Group B:
cognitive training, transfer training
(Plus to reach same amount of training time of group C, relaxation and occupational training).
therapists and neuropsychologists.
Period2: 6mo, with fami- ly/caregiver collaboration (after receiving education), training pro- grammes adapted to individual home settings.
More specifically:
COGNITIVE TRAINING:
• 60’ lessons
• 4 times/wk
• individual sessions
• min. 14 sessions/pt
• cognitive program individually tailored on pt’s needs.
TRANSFER TRAINING:
• ADLs in different settings,
• 3 times/wk,
• total 10 sessions
• 90’duration each.
MOTOR TRAINING:
• 60’ sessions
• 10-12 sessions
• games and tasks (e.g. orienta- tion);
• dual tasks (walk and bounce or throw a ball);
• parcours w/obstacles;
• Aerobic activities including treadmill walking in winter and Nordic walking in summer
• during the 2nd phase at home, caregiver received instructions how
from one group to the other.
Group C:
cognitive training, transfer training, psychomotor training.
to organize the sessions, so that 40% outdoor and 60% gym
All the training programs were carried out having the patients in the “on” stage.
7) ”Intensive Rehabilita- tion Increases BDNF Serum Levels in Parkin- sonian Patients: a Ran- domized Study”
(Frazzitta, 2014)
Randomized Study
9 SUBJECTS:
• Average age 67±5
• Idiopathic PD. similar duration (approx. 8 yrs)
• H&Y 1-1,5.
• Rasagiline treatment.
• No other neurological comorbidi- ty.
• Mini mental state examination
>26.
• Vision and hearing sufficient to understand the instructions.
• Walking w/out physical assis- tance.
METHODS:
• 2 groups, treatment group and non-treatment/control group.
• 4 weeks therapy.
• 3 daily sessions (2 in the morn- ing, 1 in the afternoon).
• 1 hour duration/session.
• 5 days/week.
• 3 session/day, 1 hour each.
SESSION 1:
Cardiovascular warm up, ROM spinal, pelvic and scapular joints, strengthen- ing abdominal wall, postural changes from supine, stretching, relax.
SESSION 2:
• balance training on stabilometric plat- form + visual cue;
• gait training on treadmill plus (visual and auditory cue), HRreserve ≥60% for 30’every day for 4wks.
SESSION 3:
Occupational therapy for ADL: trans- fers, rolling in bed, dressing, tool us- age, hand skills.
No treatment.
(*) = This article, being a single case report, is not particularly suitable to be graded according to the PEDro scale.
Table 3. Assessment tests, study results and eventual reasons of bias.
Study (Title, Authors and
Year )
Assessment Results Bias/Discussion
1) ”Benefits of phys- ical exercise on ex- ecutive functions in older people with Parkinson’s Disease”
(Tanaka, 2009)
• Wisconsin card sorting test (execu- tive functions).
• Wechsler adult intelligence scale III (concentrated attention).
• State trait anxiety inventory (anxie- ty).
• Hospital anxiety and depression scale (depressive symptoms, not the anxiety part)
As shown by the Wisconsin card sorting test, the study group improved in the executive functions, particularly in the variables:
“Categories completed” (telling about the abil- ity to concentrate on specific aspect and ignore others)
“Perseverative errors” (index of mental flexi- bility). This was not the case of the control group.
Both the groups showed no significant improve- ment in the “Confounding variables” (concentrated attention, state anxiety and depressive symptoms) = the improvement in the Executive Functions regis- tered in the sample group was not due to a change in confounding variables, but strictly to the exercise regimen.
I. Procedure was not purely random.
II. Not enough HR monitors for the control group sessions.
III. Although further explanation of the exercise sessions is available in the article, still the very exercises instructed are not illustrated.
2) “Phase I/II ran- domized trial of aer- obic exercise in Par- kinson’s disease in a community setting”
(Uc, 2014)
• Eriksen flanker task (primary cogni- tive measurement)
• Stroop test (inhibition of secondary stimuli).
• Wisconsin Card Sorting test (set shifting).
• Trail making test (set shifting).
• Judgement of line orientation (visual perception).
• Complex figure test-copy (visual perception).
• Rey auditory verbal learning test (verbal memory).
Improvements in different categories have been reported:
1. Aerobic fitness and motor function;
2. Cognition (flanker test);
3. Quality of life and other non-motor functions.
Concerning cognitive improvements, those were mostly in the area of inhibition (selective cognitive improvement).
I. NO control group: efficacy of the implementa- tion cannot be proven; still, the authors claimed that this phase of their on-going study provided indications more on safety, tolerability and gen- eral feasibility for a future phase three of this study.
II. The study design was partially modified throughout the years, in particular:
“Group setting”: no randomization was pos- sible, due to logistical factors (rural residence of the patients); for this reason, the “group setting” was abandoned after the first year of
